The chronic use or abuse of pentobarbital or methadone leads to drug dependence, and the withdrawal from pentobarbital often is so severe that it can only be done gradually. Acute administration of these drugs affects brain monoamines, and the physiological dependence and subsequent withdrawal symptoms associated with termination of drug administration appear to be partially related to an effect on brain biogenic monoamines. Although the chronic use of these drugs leads to dependence, almost all the studies related to their effects on brain monoamines have been acute studies. Sensitive biochemical and fluorescence procedures will be utilized to study the effects of pentobarbital or methadone on the content and turnover of serotonin, dopamine and noradrenaline in six discrete areas of the rat brain. Turnover of these brain amines will be determined by both pharmacological and radioisotopic procedures. The blood levels of pentobarbital and methadone will be determined by gas chromatographic procedures. Correlations between blood levels of drug and the effects on brain monoamines will provide (1) a clearer index of the level of addiction of each animal and (2) a reference to predict the effect of a certain blood level of pentobarbital or methadone on brain monoamines in the drug dependent human. Pharmacological studies will explore the relationship between the chronic drug effects on brain amines and the development of dependence or of the abstinence syndrome after withdrawal. Information gained from these studies will be of use in the development of new therapeutic methods for the treatment of behavioral and neurological disorders associated with pentobarbital or methadone dependence and withdrawal.